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Severe Polycystic Liver Disease Is Not Caused by Large Deletions of the PRKCSH Gene.

ABSTRACT: BACKGROUND:Isolated polycystic liver disease (ADPLD) is an autosomal dominant Mendelian disorder. Heterozygous PRKCSH (where PRKCSH is protein kinase C substrate 80K-H (80 kDa protein, heavy chain; MIM*177060) mutations are the most frequent cause. Routine molecular testing using Sanger sequencing identifies pathogenic variants in the PRKCSH (15%) and SEC63 (where SEC63 is Saccharomyces cerevisiae homolog 63 (MIM*608648); 6%) genes, but about approximately 80% of patients meeting the clinical ADPLD criteria carry no PRKCSH or SEC63 mutation. Cyst tissue often shows somatic deletions with loss of heterozygosity that was recently recognized as a general mechanism in ADPLD. We hypothesized that germline deletions in the PRKCSH gene may be responsible for hepatic cystogenesis in a significant number of mutation-negative ADPLD patients. METHODS:In this study, we designed a multiplex ligation-dependent probe amplification (MLPA) assay to screen for deletions of PRKCSH exons. Genomic DNA from 60 patients with an ADPLD phenotype was included. RESULTS:MLPA analysis detected no exon deletions in mutation-negative ADPLD patients. CONCLUSION:Large copy number variations on germline level are not present in patients with a clinical diagnosis of ADPLD. MLPA analysis of the PRKCSH gene should not be considered as a diagnostic method to explain hepatic cystogenesis.

SUBMITTER: Cnossen WR

PROVIDER: S-EPMC6807128 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Severe Polycystic Liver Disease Is Not Caused by Large Deletions of the PRKCSH Gene.

Cnossen Wybrich R WR Maurits Jake S F JS Salomon Jody J Te Morsche René H M RH Waanders Esmé E Drenth Joost P H JP

Journal of clinical laboratory analysis 20150913 5

<h4>Background</h4>Isolated polycystic liver disease (ADPLD) is an autosomal dominant Mendelian disorder. Heterozygous PRKCSH (where PRKCSH is protein kinase C substrate 80K-H (80 kDa protein, heavy chain; MIM*177060) mutations are the most frequent cause. Routine molecular testing using Sanger sequencing identifies pathogenic variants in the PRKCSH (15%) and SEC63 (where SEC63 is Saccharomyces cerevisiae homolog 63 (MIM*608648); 6%) genes, but about approximately 80% of patients meeting the cli ...[more]

PMID: 26365003

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Project description:We showed in a randomized double-blinded placebo-controlled clinical trial that octreotide long-acting repeatable depot.® (OctLAR(®)) for 12 months reduces kidney and liver growth in autosomal dominant polycystic kidney patients with severe polycystic liver disease (PLD) and liver growth in patients with severe isolated PLD. We have now completed an open-label extension for one additional year to assess safety and clinical benefits of continued use of OctLAR for 2 years (O ? O) and examined drug effect in the placebo group who crossed over to OctLAR in Year 2 (P ? O).The primary end point was change in total liver volume (TLV) measured by magnetic resonance imaging (MRI); secondary end points were changes in total kidney volume (TKV) measured by MRI, glomerular filtration rate (GFR), quality of life (QOL), safety, vital signs and laboratory parameters.Forty-one of 42 patients received OctLAR (n = 28) or placebo (n = 14) in Year 1 and received OctLAR in Year 2 (maximum dose 40 mg). Patients originally randomized to placebo (P ? O) showed substantial reduction in TLV after treatment with OctLAR in Year 2 (?% -7.66 ± 9.69%, P = 0.011). The initial reduction of TLV in the OctLAR group (O ? O) was maintained for 2 years (?% -5.96 ± 8.90%), although did not change significantly during Year 2 (?% -0.77 ± 6.82%). OctLAR inhibited renal enlargement during Year 1 (?% +0.42 ± 7.61%) in the (O ? O) group and during Year 2 (?% -0.41 ± 9.45%) in the (P ? O) group, but not throughout Year 2 (?% +6.49 ± 7.08%) in the (O ? O) group. Using pooled analyses of all individuals who received OctLAR for 12 months, i.e. in Year 1 for O ? O patients and Year 2 for P ? O patients, average reduction in TLV was -6.08 ± 7.58% (P = 0.001) compared to net growth of 0.9 ± 8.35% in the original placebo group. OctLAR-treated individuals continued to experience improvements in QOL in Year 2, although overall physical and mental improvements were not significant during Year 2 compared to Year 1. Changes in GFR were similar in both groups.Over 2 years, OctLAR significantly reduced the rate of increase in TLV and possibly the rate of increase in TKV.

Dataset Information

Severe Polycystic Liver Disease Is Not Caused by Large Deletions of the PRKCSH Gene.

Publications

Severe Polycystic Liver Disease Is Not Caused by Large Deletions of the PRKCSH Gene.

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